Treatment of Locally Advanced Rectal Cancer: Turning Good Rationale Into Good Evidence?

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Locally advanced rectal cancer is one of the most difficult management challenges in colorectal surgery. The traditional paradigm of radical surgery and chemoradiotherapy was established decades ago, although it was long ago recognized that the sequencing of neoadjuvant therapy followed by surgery improved outcomes and decreased the rate of incomplete resection and recurrence.1 However, it has become increasingly clear that some patients belong to a particularly high-risk group, and a one-size-fits-all strategy is not optimal. There is a need to identify multidisciplinary strategies that address both issues of systemic and local control, maximizing the potential for treatment success and survival.
In this report of the French Research Group of Rectal Cancer Surgery trial, the investigators have attempted to provide insight into how to address this treatment dilemma with a 4-arm randomized phase II trial that simultaneously asks questions regarding the role of systemic chemotherapy intensification, need for radiotherapy, and role of radiation dose intensification.2 Patients with locally advanced circumferential resection margin (CRM) at-risk tumors received induction systemic chemotherapy with the highly active 3-drug combination of 5-fluorouracil, oxaliplatin, and irinotecan. Patients exhibiting a good response to therapy were randomly assigned to primary surgery vs chemoradiotherapy (50 Gy), and those not achieving a good response were randomly assigned to chemoradiotherapy with or without dose intensification (50 vs 60 Gy). This is a complex trial design that at once incorporates multiple imbedded questions. It assumes the value of induction therapy and additional benefit with the triplet combination, both strategies with considerable rationale but neither based on previous randomized evaluation in the setting of primary disease.3,4 Furthermore, the lower-than-anticipated rate of major regression to induction therapy led to an early termination of the trial. This study highlights the difficulties in determining the optimal comparative study designs to help push the needle forward in the management of patients with locally advanced rectal cancer and the sometimes-difficult challenge of reconciling the parallel strategies of systemic treatment intensification, radiotherapy dose intensification, and avoidance of overtreatment currently being more broadly considered in the field of rectal cancer.
There are several reasons to consider the induction alternative to the traditional paradigm of surgery before systemic chemotherapy. Although advances in the evaluation and treatment of rectal cancer along with the increased awareness of the importance of surgical quality control have largely solved the problem of local recurrence, systemic disease failure remains a significant problem. Although adjuvant chemotherapy has the potential to decrease the risk of distant recurrence, treatment-related toxicities often result in delays or lack of receipt of therapy.5 Particularly for patients at high risk for systemic failure, induction therapy has the potential to improve disease control with earlier initiation of treatment, higher rates of treatment completion, and lower rates of treatment-associated toxicity.6 In addition, systemic chemotherapy can result in significant regression of the primary tumor and associated lymph nodes as demonstrated by the postinduction conversion of patients from CRM at-risk to CRM clear or N+ to N– disease, although complete regression events are less common, with only 15% of the patients in this study achieving >75% regression after induction therapy. Not surprisingly, as with radiotherapy response, lower initial tumor burden was one factor associated with treatment response.
The role of radiotherapy dose intensification remains another unanswered question. It is now generally accepted that a 5.4-Gy boost to the primary tumor in addition to the standard 45.0 Gy to the whole pelvis improves treatment response and is safe. In this study, there appeared to be a higher rate of R0 resection (88% (95% CI, 77%–95%) vs 83% (95% CI, 72%–91%)) with a 16.0-Gy vs 6.
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